EP0476944B1 - Aromatase inhibiting 4(5)-imidazoles - Google Patents

Aromatase inhibiting 4(5)-imidazoles Download PDF

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Publication number
EP0476944B1
EP0476944B1 EP91308407A EP91308407A EP0476944B1 EP 0476944 B1 EP0476944 B1 EP 0476944B1 EP 91308407 A EP91308407 A EP 91308407A EP 91308407 A EP91308407 A EP 91308407A EP 0476944 B1 EP0476944 B1 EP 0476944B1
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EP
European Patent Office
Prior art keywords
formula
compound
substituents
give
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP91308407A
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German (de)
English (en)
French (fr)
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EP0476944A1 (en
Inventor
Arto Johannes Karjalainen
Arja Marketta Kalapudas
Reino Olavi Pelkonen
Marja-Liisa Sodervall
Matti Antero Lahde
Risto Arvo Sakari Lammintausta
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Orion Oyj
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Orion Yhtyma Oy
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine

Definitions

  • the present invention relates to substituted imidazole derivatives and their non-toxic, pharmaceutically acceptable acid addition salts, and their preparation, to pharmaceutical compositions containing the same and their use.
  • EP-A-0 194 984 discloses imidazole derivatives that have ⁇ 2-blocking and/or anti-convulsive activities which are said to be utilisable as therapeutic agents.
  • EP-A-0 311 447 discloses imidazole derivatives which are said to exhibit pharmacological properties, especially aromatase inhibiting effects and are said to be useful in the treatment of estrogen dependent diseases, e.g. breast cancer.
  • EP-A-0 165 779 discloses aromatase inhibiting 4(5)-substituted imidazole derivatives, a process for preparing them, their use to inhibit aromatase or to treat or prevent estrogen dependent disease, and pharmaceutical formulations comprising the derivatives as active ingredient.
  • EP-A-0 390 558 which was published on 3 October 1990 discloses imidazole derivatives which are said to exhibit aromatase and desmolase inhibiting properties and it suggests that very selective aromatase inhibiting compounds are valuable in the treatment of estrogen dependent diseases, e.g. breast cancer.
  • the imidazole derivatives of the present invention have the general formula (I): wherein R1, R2, R'1 and R'2, which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, NO2, NH2, CN, CF3, CHF2, CH2F or halogen; R' is H or where R3 is H, CH3 or halogen; R4 is H or OH and R5 is H or OH or R4 and R5 together form a bond and n is 1 to 4.
  • the compounds of formula (I) form acid addition salts with both organic and inorganic acids. They can thus form many pharmaceutically usable acid addition salts, as for instance, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
  • R1, R2, R'1 and R'2 are H, CN or halogen, especially H, CN or F.
  • the phenyl groups may be substituted in the ortho, meta or para position. If a phenyl group is mono-substituted, it is preferably substituted in the para-position.
  • R' is H; preferably R4 and R5 are each H.
  • the invention includes within its scope pharmaceutical compositions comprising at least one compound of formula (I) or a non-toxic pharmaceutically acceptable salt thereof, and a compatible pharmaceutically acceptable carrier therefor.
  • the compounds of the present invention have been found, depending on the substituents R', R1, R2, R'1 and R'2, to possess varying degrees of aromatase and desmolase inhibiting properties. Among them there are very selective enzyme aromatase inhibiting compounds which are valuable in the treatment of estrogen dependent diseases, e.g. breast cancer or benign prostatic hyperplasia (BPH).
  • the present invention also provides compounds of formula (I) or non-toxic pharmaceutically acceptable acid addition salts thereof for use in a method of medical treatment.
  • the present invention further provides the use of compound of formula (I) or non-toxic pharmaceutically acceptable acid addition salts thereof in the manufacture of a medicament for the inhibition of aromatase.
  • Compounds of formula (I) can be prepared by McMurry reaction which comprises a reductive coupling of a diphenylketone (II) wherein R1, R2, R'1 and R'2, which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, NH2, CN, CF3, CHF2, CH2F or halogen and n is 1-4, and an 4(5)-imidazole aldehyde (III) wherein R' is as defined before, in an appropriate solvent, e.g. tetrahydrofuran or dimethoxyethane, in the presence of a low valent titanium reagent in an inert atmosphere, e.g.
  • reaction scheme for this step can be illustrated as follows: If R' is a substituted or unsubstituted benzyl, this group may be removed by hydrogenation as well. In this case the hydrogenation is performed in an acidic medium such as hydrochloric acid-ethanol mixture.
  • the ketone of formula (II) can be prepared for example from an appropriately substituted acetophenone and benzaldehyde by condensation and hydrogenation.
  • Another method of preparing compounds of formula (I) is a reaction which comprises reacting a ketone of formula (VII) wherein R' and n are as defined before and R1 and R2, which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, NO2, CF3, CHF2, CH2F or halogen, with an appropriate halide derivative of the formula (VIII) wherein R'1 and R'2, which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, NO2, CF3, CHF2, CH2F or halogen, in the presence of an alkyl lithium, such as n-butyl lithium, or magnesium in an appropriate solvent, such as tetrahydrofuran, to give compounds of formula (IX) wherein R', R1, R2, R'1, R'2 and n are as defined for formulae (VII) and (VIII).
  • Compounds of formula (VII) can be prepared e.g. from an 4(5)-imidazole acetaldehyde and an appropriate arylalkylhalide and then oxidizing.
  • Compounds of formula (I) wherein one or more of the substituents R1, R2, R'1 and R'2 are CN can also be prepared by refluxing compounds of formula (IX) wherein one or more of the substituents are a tert-butylaminocarbonyl group or an oxazoline group (IX') with e.g. SOCl2, POCl3 or PCl5 optionally in an appropriate solvent, such as acetonitrile, to give compounds of formula (I) wherein R' is a benzyl group, R4 and R5 form together a bond and one or more of the substituents R1, R2, R'1 and R'2 are CN.
  • the substituents that are not CN are H, CH3, C2H5, C3H7, OCH3, CF3, CHF2, CH2F or halogen.
  • the unsaturated compounds are hydrogenated by the methods described before.
  • Compounds of formula (X) wherein one or more of the substituents are a tert-butylaminocarbonyl or an oxazoline group (X') may be dehydrated by e.g. SOCl2, POCl3 or PCl5 as described before to form compounds of formula (XI) wherein one or more of the substituents R1, R2, R'1 and R'2 are CN and the substituents that are not CN are H, CH3, C2H5, C3H7, OCH3, CF3, CHF2, CH2F or halogen.
  • Another method to give compounds of formula (I) wherein the substituents are as defined for formula (XI) is refluxing compounds of formula (IX') or (X'), in an appropriate solvent, such as dichloromethane, in the presence of SOCl2 to give compounds of formula (IV) wherein R' is H or a protecting group and the substituents R1, R2, R'1 and R'2 are as defined for formula (X').
  • the unsaturated compounds are further reacted by a hydrogen transfer reaction or hydrogenated to give compounds of formula (VI) wherein the substituents are as defined for formula (X') which are further reacted with e.g. SOCl2 to give compounds of formula (I) wherein the substituents are as defined for formula (XI).
  • the compounds of formula (I) wherein one or more of the substituents are CN can be prepared from the corresponding compounds where one or more of the substituents R1, R2, R'1 and R'2 are NH2 by diazotization.
  • Another method for the preparation of compounds of formula (IV) is the reaction of a diphenylhalogen compound (XIV) wherein R1, R2, R'1 and R'2, which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, NO2, CF3, CHF2, CH2F or halogen, n is 1 to 4 and Hal is halogen, with an 4(5)-imidazole aldehyde (III) using n-butyllithium as a reagent to give compounds of formula (XV)
  • the compounds of formula (XV) may be dehydrated to give the compounds of formula (IV) wherein the substituents R1, R2, R'1 and R'2, which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, NO2, CF3, CHF2, CH2F or halogen.
  • the compounds of formula (IV) wherein one or more of the substituents are CN may be prepared by the same method when the CN-group(
  • Still another method for preparing of compounds of formula (I) is a process which comprises a Reformatskii reaction of the 4(5)-imidazole aldehyde (III) with an ester of ⁇ -bromophenylacetic acid (VXI) wherein R'1 and R'2, which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, NO2, CF3, CHF2, CH2F or halogen and R is a lower alkyl, to give an ester of ⁇ -hydroxy- ⁇ -phenylimidazolepropionic acid (XVII)
  • the compounds of formula (XVII) can be dehydrated and hydrogenated to give the saturated ⁇ -phenylimidazolepropionic acid esters (XVIII) which can be reduced to aldehydes of formula (XIX) or converted to amides of formula (XX) wherein R3 and R4 are lower alkyl or N, R3 and R4 together form a ring.
  • R1, R2, R'1 and R'2 which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, NH2, CN, CF3, CHF2, CH2F or halogen.
  • the compounds of formula (I), their non-toxic, pharmaceutically acceptable acid addition salts or mixtures thereof may be administered parenterally, intravenously or orally.
  • an effective amount of the compound is combined with a suitable pharmaceutical carrier.
  • the term "effective amount” encompasses those amounts which yield the desired activity without causing adverse side-effects.
  • the precise amount employed in a particular situation is dependent upon numerous factors such as method of administration, type of mammal, condition for which the compound is administered, etc., and of course the structure of the compound.
  • the pharmaceutical carriers which are typically employed with the compounds of the present invention may be solid or liquid and are generally selected with the planned manner of administration in mind.
  • solid carriers include lactose, sucrose, gelatin and agar
  • liquid carriers include water, syrup, peanut oil and olive oil.
  • suitable carriers are well known to those skilled in the art of pharmaceutical formulations.
  • Other combination of the compound and the carrier may be fashioned into numerous acceptable forms, such as tablets, capsules, suppositories, solutions, emulsions and powders.
  • the compounds of the invention are especially valuable as aromatase inhibiting agents and are therefore useful in the treatment of estrogen dependent diseases, e.g. breast cancer or benign prostatic hyperplasia (BPH).
  • estrogen dependent diseases e.g. breast cancer or benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • Estrogens are essential steroids in the physiology and function of normal development of breast and sex organs in women.
  • estrogens are known to stimulate the growth of estrogen dependent cancers, especially breast and endometrial cancers, and they may increase the risk of development of breast cancer if given at pharmacological doses for a long time. Excessive production of estradiol may also cause other, benign disorders in hormone dependent organs.
  • the importance of estrogens as cancer growth stimulators and/or regulators is clearly stressed by the fact that antiestrogens have reached a central position in the treatment of estrogen receptor rich breast cancers. Antiestrogens act by binding to estrogen receptors and thereby inhibiting the biological effect of estrogens.
  • Cholesterol side chain cleavage (SCC) activity was measured according to the method of Pasanen and Pelkonen (Steroids 43:517-527, 1984). Incubations were carried out in 1,5 ml Eppendorf plastic tubes, and an Eppendorf shaker, centrifuge and incubator were used as a unit. In a 300 ⁇ l incubation volume, the substrate (5 ⁇ M) was prepared according to Hanukoglu and Jefcoate (J. Chromatogr.
  • the daily dose for a patient varies from about 20 to about 200 mg, administered orally.
  • LD50 acute toxicity
  • Toluene is added and the mixture is filtered through siliceous earth.
  • the toluene phase is separated and the water layer is extracted again with toluene.
  • the toluene extracts are combined, washed with water, dried with MgSO4 and evaporated to dryness.
  • the crude product is purified by flash chromatography with methylene chloride and methanol (9,75:0,25) as eluent.
  • 1-benzyl-5-[2-(4-cyanophenyl)-4-(4-fluorophenyl)-1-butenyl]-1H-imidizole hydrochloride is dissolved in ethanol and a catalytic amount of 10 % Pd/C is added.
  • the reaction mixture is agitated vigorously at room temperature in a hydrogen atmosphere until the reduction and the debenzylation are complete.
  • the reaction mixture is filtered and evaporated to dryness.
  • the product is purified by flash chromatography.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)
EP91308407A 1990-09-21 1991-09-13 Aromatase inhibiting 4(5)-imidazoles Expired - Lifetime EP0476944B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9020629A GB2248058B (en) 1990-09-21 1990-09-21 Aromatase inhibiting 4(5)-imidazoles
GB9020629 1990-09-21

Publications (2)

Publication Number Publication Date
EP0476944A1 EP0476944A1 (en) 1992-03-25
EP0476944B1 true EP0476944B1 (en) 1995-11-15

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EP91308407A Expired - Lifetime EP0476944B1 (en) 1990-09-21 1991-09-13 Aromatase inhibiting 4(5)-imidazoles

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EP (1) EP0476944B1 (cs)
JP (1) JPH04230668A (cs)
AT (1) ATE130295T1 (cs)
AU (1) AU640817B2 (cs)
CA (1) CA2051803A1 (cs)
CZ (1) CZ280088B6 (cs)
DE (1) DE69114644T2 (cs)
FI (1) FI914254A7 (cs)
GB (1) GB2248058B (cs)
HU (1) HUT59107A (cs)
IE (1) IE68934B1 (cs)
IL (1) IL99472A (cs)
LT (1) LT3441B (cs)
LV (1) LV10095B (cs)
NO (1) NO913712L (cs)
NZ (1) NZ239800A (cs)
PL (1) PL167741B1 (cs)
PT (1) PT99019A (cs)
RU (1) RU2036193C1 (cs)
ZA (1) ZA917476B (cs)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9125924D0 (en) * 1991-06-18 1992-02-05 Orion Yhtymae Oy Stereoisomers of an imidazole derivative
GB9224144D0 (en) * 1992-11-18 1993-01-06 Erba Carlo Spa Phenyl-imidazolidinone derivatives and process for their preparation
WO2009082268A2 (ru) * 2007-12-21 2009-07-02 Alla Chem, Llc ЛИГАНДЫ α-АДРЕНОЦЕПТОРОВ, ДОПАМИНОВЫХ, ГИСТАМИНОВЫХ, ИМИДАЗОЛИНОВЫХ И СЕРОТОНИНОВЫХ РЕЦЕПТОРОВ И ИХ ПРИМЕНЕНИЕ

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4605661A (en) * 1984-06-18 1986-08-12 Eli Lilly And Company Aromastase inhibiting α,α-diarylimidazole-4(5)-propionitriles, α,α-diarylimidazole-4(5)-propionamides, and 4(5)-(2,2-diarylethyl)imidazoles
LU85747A1 (fr) * 1985-01-28 1986-08-04 Continental Pharma Derives d'imidazole leur preparation et utilisation ainsi que les compositions pharmaceutiques contenant des derives
GB2210875B (en) * 1987-10-09 1991-05-29 Farmos Oy Aromatase inhibiting 4(5)-imidazoles
GB8818561D0 (en) * 1988-08-04 1988-09-07 Ici Plc Diphenylethane derivatives
GB2231568B (en) * 1989-03-31 1992-07-08 Farmos Oy New aromatase inhibiting 4(5)-imidazoles
GB2229719B (en) * 1989-03-30 1992-04-29 Farmos Oy Novel aromatase inhibiting 4(5)-imidazoles
JPH032168A (ja) * 1989-03-30 1991-01-08 Farmos Yhtymae Oy アロマターゼ阻害活性を有する新規な４（５）―イミダゾール

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Publication number Publication date
LT3441B (en) 1995-10-25
IL99472A (en) 1995-11-27
AU640817B2 (en) 1993-09-02
NO913712L (no) 1992-03-23
RU2036193C1 (ru) 1995-05-27
DE69114644D1 (de) 1995-12-21
IL99472A0 (en) 1992-08-18
CZ280088B6 (cs) 1995-10-18
GB9020629D0 (en) 1990-10-31
PT99019A (pt) 1992-08-31
EP0476944A1 (en) 1992-03-25
CA2051803A1 (en) 1992-03-22
HU913019D0 (en) 1992-01-28
PL167741B1 (pl) 1995-10-31
ATE130295T1 (de) 1995-12-15
JPH04230668A (ja) 1992-08-19
PL291747A1 (en) 1992-10-19
FI914254A7 (fi) 1992-03-22
NO913712D0 (no) 1991-09-20
LTIP582A (en) 1994-12-27
LV10095B (en) 1995-02-20
IE68934B1 (en) 1996-07-24
FI914254A0 (fi) 1991-09-10
GB2248058B (en) 1994-09-14
DE69114644T2 (de) 1996-05-15
IE913314A1 (en) 1992-02-25
GB2248058A (en) 1992-03-25
ZA917476B (en) 1992-05-27
LV10095A (lv) 1994-05-10
NZ239800A (en) 1993-11-25
HUT59107A (en) 1992-04-28
AU8382691A (en) 1992-04-09
CS286891A3 (en) 1992-04-15

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